Unbiased expression mapping identifies a link between the complement and cholinergic systems in the rat central...

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• The complement system is implicated in central nervous system (CNS) diseases and synaptic terminal elimination.
• Mechanisms regulating complement activation within the CNS remain poorly understood.
• Synaptic terminal loss post-nerve injury varies between rat strains, linked to complement components C1q and C3.

Purpose of the Study:

• To identify genetic pathways regulating complement expression in the CNS.
• To investigate the relationship between cholinergic activity and complement activation.

Main Methods:

• Genome-wide expression profiling and linkage analysis in an F2(DA × PVG) intercross.
• Coexpression network analysis to identify regulatory pathways.
• In vitro stimulation of rat and mouse glia with TNF-α and acetylcholine.

Main Results:

• Quantitative trait loci regulating C1qa, C1qb, C3, and C9 expression were identified.
• C3 expression was linked to butyrylcholinesterase and regulated independently of C1q, C1qb, and C9.
• Acetylcholine dose-dependently abrogated TNF-α-induced C3 expression in glia.

Conclusions:

• Novel pathways regulating CNS complement expression, influenced by genetic variability, have been identified.
• A direct link between cholinergic activity and complement activation, specifically C3, was demonstrated.
• Findings are relevant for understanding neurodegenerative conditions involving neuronal injury and complement activation.